Rbap48 Protein, a Critical Component Of Gpr158/Osteocalcin Signaling, Ameliorates Age-Related Memory Loss

Deciphering the precise molecular mechanisms of Age-Related Memory Loss is of great importance for developing appropriate therapeutic interventions. We have previously found that the histone binding protein RbAp48/Rbbp4, whose levels decline linearly with age in healthy humans, is a molecular determinant of Aged-Related Memory Loss. In an effort to explore how this histone binding protein regulates the genomic landscape in the hippocampal circuit, we studied RbAp48 and found that it controls the expression of BDNF and GPR158 proteins, both critical components of Osteocalcin signaling in the mouse hippocampus. We find that inhibition of RbAp48 in the hippocampal formation renders ineffective Osteocalcin’s beneficial functions in cognition and actively causes deficits in discrimination memory. In turn, disruption of Osteocalcin/GPR158 signaling leads to the downregulation of RbAp48 protein mimicking the discrimination memory deficits observed in the aged hippocampus. We also find that activation of the Osteocalcin/GPR158 pathway increases the expression of RbAp48 in the aged dentate gyrus and rescues Aged Related Memory Loss.